The invention disclosed herein is directed to certain spiro-substituted azacycles useful as tachykinin receptor antagonists. In particular, the compounds disclosed herein are neurokinin receptor antagonists.
The tachykinins, substance P (SP), neurokinin A (NKA) and neurokinin B (NKB), are structurally similar members of a family of neuropeptides. Each of these is an agonist of the receptor types, neurokinin-1 receptor NK-1), neuorokinin-2 receptor (NK-2) and neuorokinin-3 receptor (NK-3), which are so defined according to their relative abilities to bind tachykinins with high affinity and to be activated by the natural agonists SP, NKA and NKB respectively.
The tachykinins are distinguished by a conserved carboxyl-terminal sequence Phe-X-Gly-Leu-Met-NH.sub.2. More specifically, substance P is a pharmacologically-active neuropeptide that is produced in mammals and possesses a characteristic amino acid sequence:
Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH.sub.2 PA1 His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH.sub.2. PA1 Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH.sub.2. PA1 k is 0, 1 or 2; PA1 l and m are each independently 0, 1, 2, 3, 4, or 5, with the proviso that l+m is equal to 1, 2, 3, 4, or 5; PA1 R.sub.1 is selected from a group consisting of: PA1 X is carbon, and PA1 R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are independently selected from a group consisting of: PA1 R.sup.2 and R.sup.3, or R.sup.3 and R.sup.4, together form a carbon-carbon bond, or PA1 R.sup.2, R.sup.3 and R.sup.4 are defined as above, and X--R.sup.5 is oxygen or S--(O).sub.i, where i=0, 1, or 2. PA1 k is 0, 1 or 2; PA1 l and m are each independently 0, 1, 2, 3, 4, or 5, with the proviso that l+m is equal to 1, 2, 3, 4, or 5; PA1 R.sub.1 is selected from a group consisting of: PA1 (a) hydrogen, PA1 (b) C.sub.1-6 alkyl, or mono or disubstituted C.sub.1-6 alkyl, the substitutents independently selected from PA1 (c) phenyl or naphthyl or mono di or trisubstituted phenyl or naphthyl, the substitutents independently selected from PA1 R.sub.6 is defined as above and R.sub.6 and R.sub.7 are joined together with the nitrogen to which they are attached to form a 5-, 6-, or 7-membered monocyclic saturated ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and in which the ring is unsubstituted or mono or disubstituted, the substituents independently selected from PA1 (8) --NR.sub. CO.sub.2 R.sub.7, PA1 (9) --NR.sub.6 CONHR.sub.7, PA1 (10) --NR.sub.6 S(O).sub.j R.sub.7, wherein j is 1 or 2, PA1 (11) --CONR.sub.6 R.sub.7, PA1 (12) --COR.sub.6, PA1 (13) --CO.sub.2 R.sub.6, PA1 (14) --OR.sub.6, PA1 (15) --S(O).sub.k 'R.sub.6 wherein k' is 0, 1 or 2, PA1 (16) heteroaryl, wherein heteroaryl is selected from the group consisting of: PA1 wherein the heteroaryl is unsubstituted or mono di or trisubstituted, the substituents independently selected from, PA1 X is carbon, and PA1 R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are independently selected from a group consisting of: PA1 (a) hydrogen, PA1 (b) C.sub.1-6 alkyl, branched or unbranched, unsubstituted or mono PA1 (c) hydroxy PA1 (d) oxo PA1 (e) OR.sub.6, wherein R.sub.6 is as defined immediately above, PA1 (f) halogen, PA1 (g) trifluoromethyl, PA1 (h) nitro, PA1 (i) cyano, PA1 (j) NHR.sub.6, PA1 (k) NR.sub.6 R.sub.7, PA1 (l) NHCOR.sub.6, PA1 (m) NR.sub.6 COR.sub.7, PA1 (n) NHCO.sub.2 R.sub.6, PA1 (o) NR.sub.6 CO.sub.2 R.sub.7, PA1 (p) NHS(O).sub.j R.sub.6, PA1 (q) NR.sub.6 S(O).sub.j R.sub.7, PA1 (r) CONR.sub.6 R.sub.7, PA1 (s) COR.sub.6, PA1 (t) CO.sub.2 R.sub.6, PA1 (u) S(O).sub.k 'R.sub.6, PA1 (v) heteroaryl, wherein heteroaryl is selected from the group consisting of: PA1 (1) hydrogen, PA1 (2) C.sub.1-6 alkyl, branched or unbranched, unsubstituted or mono PA1 (3) hydroxy PA1 (4) oxo PA1 (5) OR.sub.6, PA1 (7) trifluoromethyl, PA1 (8) nitro, PA1 (9) cyano, PA1 (10) NHR.sub.6, PA1 (11) NR.sub.6 R.sub.7, PA1 (12) NHCOR.sub.6, PA1 (13) NR.sub.6 COR.sub.7, PA1 (14) NHCO.sub.2 R.sub.6, PA1 (15) NR.sub.6 CO.sub.2 R.sub.7, PA1 (16) NHS(O).sub.j R.sub.6, PA1 (17) NR.sub.6 S(O).sub.j R.sub.7, PA1 (18) CONR.sub.6 R.sub.7, PA1 (19) COR.sub.6, PA1 (20) CO.sub.2 R.sub.6, PA1 (21) S(O).sub.k 'R.sub.6, and PA1 (22) phenyl;
Neurokinin A possesses the following amino acid sequence:
Neurokinin B possesses the following amino acid sequence:
(Chang et al., Nature New Biol. 232, 86 (1971); D. F. Veber et al., U.S. Pat. No. 4,680,283).
The neurokinin receptors are widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes. This includes sensory perception of olfaction, vision, audition and pain, movement control, gastric motility, vasodilation, salivation, and micturition (B. Pernow, Pharmacol. Rev., 1983, 35, 85-141). The NK1 and NK2 receptor subtypes are implicated in synaptic transmission (Laneuville et al., Life Sci., 42: 1295-1305 (1988)).
Substance P acts as a vasodilator, a depressant, stimulates salivation and produces increased capillary permeability. It is also capable of producing both analgesia and hyperalgesia in animals, depending on dose and pain responsiveness of the animal (see R. C. A. Frederickson et al., Science, 199, 1359 (1978); P. Oehme et al. Science, 208, 305 (1980)) and plays a role in sensory transmission and pain perception (T. M. Jessell, Advan. Biochem. Psychopharmacol. 28, 189 (1981)). In particular, substance P has been shown to be involved in the transmission of pain in migraine (see B. E. B. Sandberg et al., Journal of Medicinal Chemistry, 25, 1009 (1982)), and in arthritis (Levine et al. Science, (1984) 226 547-549).
In the airways, it has been indicated that NK1 receptors are associated with microvascular leakage and mucus secretion, while NK2 receptors regulate smooth muscle contraction. Also, it has been shown that both substance P and neurokinin A are effective in inducing airway constriction and edema. Based on such findings, it is believed that substance P and neurokinin A may be involved in the pathogenesis of neurogenic inflammation, including allergic diseases such as asthma. (Frossard et al. Life Sci., 49, 1941-1953 (1991); Advenier, et al., Biochem. Biophys. Res. Comm., 184(3), 1418-1424 (1992)).
In experimental studies, sensory neuropeptides, especially tachykinins such as substance P and neurokinin A, can bring about many of the pathophysiological features of asthma. Neurokinin A is a very potent constrictor of human airways in vitro, and substance P causes mucus secretion in the airways. (Barnes P. J., Lancet, pp242-44 (1986); Rogers D. R., Aursudkij B., Barnes P. J., Euro. J. Pharmacol, 174, 283-86 (1989)).
Inhalation of bradykinin causes bronchoconstriction in asthmatic patients but not in normal subjects. (Fuller R. W., Dixon C. M. S., Cuss F. M. C., Barnes P. J., Am Rev Respir Dis, 135, 176-80 (1987)). Since the bradykinin-induced bronchoconstriction is partly opposed by anticholinergic agents and since bradykinin is only a weak constrictor of human airways in vitro, it has been suggested that the bronchoconstrictor response is partly mediated by a neural reflex. Bradykinin stimulates vagal afferent C fibers and causes bronchoconstriction in dogs. (Kaufman M. P., Coleridge H. M., Coleridge J. C. G., Baker D. G., J. Appl. Physio., 48, 511-17 (1980)). In guinea-pig airways, bradykinin causes a bronchoconstrictor response by way of cholinergic and sensory-nerve-mediated mechanisms. (Ichinoe M., Belvisi M. G., Barnes P. J., J. Pharmacol. Exp. Ther., 253, 594-99 (1990). Bradykinin-induced bronchoconstriction in human airways may therefore be due partly to tachykinin released from sensory nerve terminals via axon reflex mechanisms. Clinical trials have shown that a dual NK-1/NK-2 antagonist (such as FK-224) protects against bradykinin induced bronchocontriction in asthmatic patients. (Ichinoe, M. et al., Lancet, vol. 340, pp 1248-1251 (1992)).
The tachykinins have also been implicated in gastrointestinal (GI) disorders and diseases of the GI tract, such as inflammatory bowel disease, ulcerative colitis and Crohn's disease, etc. (see Mantyh et al., Neuroscience, 25 (3), 817-37 (1988) and D. Regoli in "Trends in Cluster Headache" Ed. F. Sicuteri et al., Elsevier Scientific Publishers, Amsterdam, 1987, pp. 85-95).
It is also hypothesized that there is a neurogenic mechanism for arthritis in which substance P may play a role (Kidd et al., "A Neurogenic Mechanism for Symmetric Arthritis" in The Lancet, 11 Nov. 1989 and Gronblad et al., "Neuropeptides in Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis" in J. Rheumatol. (1988) 15(12) 1807-10). Therefore, substance P is believed to be involved in the inflammatory response in diseases such as rheumatoid arthritis and osteoarthritis (O'Byrne et al., in Arthritis and Rheumatism (1990) 33 1023-8). Other disease areas where tachykinin antagonists are believed to be useful are allergic conditions (Hamelet et al., Can. J. Pharmacol. Physiol. (1988) 66 1361-7), immunoregulation (Lotz et al., Science (1988) 241 1218-21, Kimball et al., J. Immunol. (1988) 141 (10) 3564-9 and A. Perianin, et al., Biochem. Biophys. Res. Commun. 161, 520 (1989)) vasodilation, bronchospasm, reflex or neuronal control of the viscera (Mantyh et al., PNAS (1988) 85 3235-9) and, possibly by arresting or slowing .beta.-amyloid-mediated neurodegenerative changes (Yankner et al., Science, (1990) 250, 279-82) in senile dementia of the Alzheimer type, Alzheimer's disease and Downs Syndrome. Substance P may also play a role in demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis J. Luber-Narod et. al., poster presented at C.I.N.P. XVIIIth Congress, 28th Jun.-2nd Jul., 1992!. Antagonists selective for the substance P and/or the neurokinin A receptor may be useful in the treatment of asthmatic disease (Frossard et al., Life Sci., 49, 1941-1953 (1991); Advenier, et al., Biochem. Biophys. Res. Comm., 184(3), 1418-1424 (1992)). These antagonists may also be useful in the treatment of emesis. See C. Bountra, K. Bounce, T. Dale, C. Gardner, C. Jordan. D. Twissell and P. Ward, Eur. J. Pharnacol., 249, R3-R4 (1993) "Anti-emetic profile of a non-peptide neurokinin NK1 receptor antagonist, CP-99,994, in the ferret.